title: microRNA-141 regulates BMI1 expression and induces senescence in human diploid fibroblasts.
abstract: Polycomb group protein BMI1 is an important regulator of senescence, aging, and cancer. On one hand, it is overexpressed in cancer cells and is required for self-renewal of stem cells. On the other hand, it is downregulated during senescence and aging. MicroRNAs have emerged as major regulators of almost every gene associated with cancer, aging, and related pathologies. At present, very little is known about the miRNAs that regulate the expression of BMI1. Here, we report that miR-141 posttranscriptionally downregulates BMI1 expression in human diploid fibroblasts (HDFs) via a miR-141 targeting sequence in the 3' untranslated region of BMI1 mRNA. We also show that overexpression of miR-141 induces premature senescence in HDFs via targeting of BMI1 in normal but not in exogenous BMI1-overexpressing HDFs. Induction of premature senescence in HDFs was accompanied by upregulation of p16INK4a, an important downstream target of BMI1 and a major regulator of senescence. Our results suggest that miR-141-based therapies could be developed to treat pathologies where BMI1 is deregulated.
authors.affiliation: Department of Biochemistry and Molecular Medicine; The George Washington University Medical Center; Washington, DC USA.
authors.forename: Manjari
authors.initials: M
authors.lastname: Dimri
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Carroll
authors.forename: Joon-Ho
authors.initials: JH
authors.lastname: Cho
authors.forename: Goberdhan P
authors.initials: GP
authors.lastname: Dimri
mesh_terms: D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004171:Diploidy; D015536:Down-Regulation; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C069077:BMI1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C533895:MIRN141 microRNA, human; D035683:MicroRNAs; D016160:Retinoblastoma Protein; D063150:Polycomb Repressive Complex 1
keywords: BMI1; aging; miR-141; microRNA; polycomb group proteins; senescence